New drug combinations

ABSTRACT

This patent application describes a new combination treatment of selective, noradrenaline-reuptake inhibitors (NARI) and specifically, reboxetine, and pindolol to provide rapid relief to patients suffering from depression, general anxiety, attention deficit hyperactivity disorder (ADHD), anxiety disorders such as obsessive compulsive disorders (OCD), panic disorders (PD), social phobia (SD) and the like.

FIELD OF THE INVENTION

[0001] This invention describes new treatments that should provide for afast acting rapid onset of relief from several nervous system disorders,and it involves the administration of the drug reboxetine in combinationwith the drug pindolol.

BACKGROUND

[0002] The introduction of tricyclic antidepressants in the early 1960shas provided a major advance in the treatment of neuropsychiatricdisorders. Reactive and endogenous depressions, diagnoses formerlycarrying grave prognostic implications, have become, with theintroduction of the tricyclics, manageable disorders with a much smallertoll on the patient and the society as a whole.

[0003] The early tricyclic compounds were reuptake inhibitors of all thecatecholamines released in the synaptic cleft, thus resulting inprolongation and enhancement of the dopamine (DA), noradrenaline (NA)and serotonin (5-hydroxytryptamine=5-HT) action. Lack of selectivityalso causes undesired side effects particularly on the acetylcholine(especially the muscarinic component), and histamine mediatedneurotransmission.

[0004] Because of these unwanted pharmacodynamic activities, cognitiveimpairment, sedation, urinary and gastrointestinal tract disturbances,increased intraocular pressure were limiting factors in the clinical useof these compounds and often required discontinuation of treatment. Ofutmost concern were also the cardiac toxic effects and the proconvulsantactivity of this group of drugs.

[0005] More recently, selective reuptake inhibitors for serotonin (SSRI)have been introduced with definite advantages in regard to fewer sideeffects without loss of efficacy.

SUMMARY OF THE INVENTION

[0006] Here we present the surprising finding that when the drugpindolol is given to a patient concurrently with a drug from a newcategory of antidepressants, a so called noradrenaline (NA) reuptakeinhibitor (NARI), the combination of drugs act with surprising speed inrelieving the symptoms of depression and it may be used for treating thesymptoms of other central nervous system disorders including, but notonly, general anxiety, Addictive Disorders, attention deficithyperactivity disorder (ADHD), anxiety disorders such as obsessivecompulsive disorders (OCD), panic disorders (PD), social phobia (SP) andthe like.

[0007] One particular NARI that is preferred is reboxetine. Reboxetineis the generic name of the pharmaceutical substance with the chemicalname of 2-(I-((2ethoxyphenoxy)benzyl)-morpholine, and itspharmaceutically acceptable salts. Reboxetine can be a free base, or itcan include reboxetine methanesulfonate (also called reboxetinemesylate) or any other pharmaceutically acceptable salt that does notsignificantly affect the pharmaceutical activity of the substance.

[0008] The chemical name of pindolol is1-(1H-Indol-4-yloxy)-3-[(1-methylethyl)amino]2-propanol;4-[2-hydroxy-3-(isopropylamino)-propoxy]indole; pinodolol. Pindolol isdescribed in U.S. Pat. No. 3,471,515, incorporated by reference andprocess steps are described in Swiss patents 469,002 and 472,404,assigned to the Sandoz Company, now the Novartis company, all documentsincorporated into this document by reference. It has the trade nameVISKEN®.

[0009] The present invention provides for the dosing of both reboxetineand pindolol, concurrently. The dosages for reboxetine and pindolol canbe measured separately. The two drugs can be given as a single combineddose or given separately. They may be given at the same or at differenttimes as long as both drugs are in the patient at one time over a 24hour period. The two drugs will preferably be given to the patient,concomitantly, concurrently, at or about the same time, within about 5,10, or 30 minutes, or they may be given within 1, 2, 3, 4, 5, 6, 8, 10,12, 18 or about 24 hours, or fractions of minutes or of hours of eachother. Concomitant or concurrent administration means the patient takesone drug within about 5 minutes of taking the other drug. Because thegoal here is to provide rapid symptomatic relief to the patient, in mostcases when treatment is started the two drugs would be administered tothe patient close in time and typically concomitantly; thereafter, thetiming of each drug's administration may not be as important.

[0010] A preferred dose range of reboxetine is 4 to 10 mg per patientper day and the more preferred dose is 6 to 8 mg or 8 to 10 mg perpatient daily, depending upon the patient, delivered twice a day(b.i.d.). The reboxetine should be given to a patient concurrently withpindolol.

[0011] A preferred dose range of pindolol is 10-60 mg per patient perday and the more preferred dose is about 10 mg per patient daily,depending upon the patient, delivered twice a day (b.i.d.). Preferablythe pindolol should be given concurrently with reboxetine as describedabove.

ADDITIONAL DESCRIPTION OF THE INVENTION AND DESCRIPTION OF THE PREFERREDEMBODIMENTS(S)

[0012] Reboxetine is the generic name of the pharmaceutical substancewith the chemical name of 2-(I-((2-ethoxyphenoxy)benzyl)-morpholine, andits pharmaceutically acceptable salts. Reboxetine can be a free base, orit can include reboxetine methanesulfonate (also called reboxetinemesylate) or any other pharmaceutically acceptable salt that does notsignificantly affect the pharmaceutical activity of the substance.Reboxetine and a method of synthesis are described in U.S. Pat. No.4,229,449, issued Oct. 21, 1980, Melloni et. al., incorporated byreference into this document, methods of preparation are described inU.S. Pat. No. 5,068,433, issued Nov. 26, 1991, Melloni et. al. and inU.S. Pat. No. 5,391,735, issued Feb. 21, 1995, both incorporated byreference. Reboxetine may also be known under the trade name ofEDRONAX™.

[0013] The pharmaceutical compositions and methods of administrationdescribed in U.S. Pat. No. 4,229,449 at col. 18, lines 33-66 arespecifically incorporated by reference. Twice a day dosing is preferredwith current formulations.

[0014] Reboxetine acts as an antidepressant. Antidepressants arefrequently grouped into categories or “generations.” The firstgeneration of antidepressants were usually tricyclic antidepressantssuch as maprotiline that affected various neurotransmitter systems andare associated with many undesirable side effects. The second generationof antidepressants, such as mianserine, mirtrazapine and trazodone arelargely devoid of anticholinergic action and their adrenolytic andantihistaminic effects are weaker. These are contrasted with the thirdgeneration of antidepressants (e.g. SSRI, ipsapirone, viloxazine,reboxetine, bupropione) that mediate only one of the three mainneurotransmitter system for depression (5-HT, noradrenaline, dopamine)and they do not affect muscarine, histamine and adrenergic cerebralsystems. Svestka, J. “Antidepressives of the 3rd, 4th and 5thgeneration,” Cesk-Psychiatr. 1994 Feb.; 90(1):3-19. (Czech).

[0015] Reboxetine, however, does not act like most antidepressants.Unlike tricyclic antidepressants and even selective serotonin reuptakeinhibitors (SSRIs), reboxetine is ineffective in the 8-OH-DPAThypothermia test, indicating that reboxetine is not a selectiveserotonin reuptake inhibitor rather it is selective for thenoradrenergic system. Thus, reboxetine is not an SSRI, rather it isconsidered a novel, selective, noradrenaline-reuptake inhibitor (NARI).Leonard-BE, “Noradrenaline in basic models of depression.”European-Neuropsychopharmacol. 1997 Apr.; 7 Suppl 1: S11-6; discussionS71-3. Unlike most drugs, reboxetine is a highly selectivenorepinephrine uptake inhibitor, with only marginal serotonin and nodopamine uptake inhibitory activity. The compound displays only weak orno anti-cholinergic activity in different animal models and is devoid ofmonoamine oxidase (MAO) inhibitory activity.

[0016] Reboxetine is highly potent and fast acting. Our investigationsindicate reboxetine has potent antireserpine activity and combines theinhibitory properties of classical tricyclic antidepressants on thereuptake of noradrenaline with an ability to desensitize

-adrenergic receptor function without showing any appreciableinteraction with muscarinic cholinergic and I-adrenerigic receptors.Moreover, reboxetine shows less vagolytic activity than other tricyclicantidepressants.

[0017] In spite of the inherently fast action of reboxetine there isstill a “lag” or delay from the time of administration of the drug untilthe time the drug provides symptomatic relief to the patient. Thetreatments described here decrease that lag time. A period of days andespecially weeks between the administration of a drug and its effect inrelieving depression can be devastating to a patient. The patient mayconclude the drug is not effective and stop taking the drug, thus aquick onset of activity is critically important for treatments of thistype. We have discovered that the combination of pinodolol andreboxetine provides highly effective relief of psychiatric disorderswith a minimal delay in onset of activity.

[0018] Pindolol is the generic name for1-(1H-Indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propanol;4-[2-hydroxy-3-(isopropylamino)-propoxy]indole; prinodolol. Pindolol isdescribed in U.S. Pat. No. 3,471,515, incorporated by reference andprocess steps are described in Swiss patents 469,002 and 472,404,assigned to the Sandoz Company, now the Novartis company, all documentsincorporated into this document by reference. It has the trade nameVISKEN®.

[0019] The dosage used to treat all of the disorders described here maybe found above and below. Reboxetine is well tolerated and has a widesafety range, it can be administered in a dose range of activeingredient from about 1 to over 40 mg/kg. It is more commonly providedin dosages of from 1 to 20 mg per patient per day. Pindolol is alsofairly safe although it is contraindicated for patients with bronchialasthmas, cardiac failure, heart block and severe bradycardia. Otheradverse reactions are possible. Pindolol dosages in the range of 5 to 60mg daily can be effective. Both compounds may be administered by anysuitable method including a convenient oral dosage form. A preferredmethod is oral dosing twice a day. The preferred dose range ofreboxetine is 4 to 20 and more preferably 4 to 10 mg per patient per dayand the preferred dose range of pindolol is 10-20 mg per patient perday. When starting medication the more preferred dose of reboxetine is 6to 8 mg or 8 to 10 mg and pindolol is 10 mg per patient daily, dependingupon the patient, delivered twice a day (b.i.d.). It can also be givenat dosages of 2, 4, 6, 8, 10 or 12 mg/patient per day or fractionsthereof: For example, suitable administrations could be 4 mg ofreboxetine and 5 mg of pindolol in the morning and 2 or 4 mg ofRebozetine and 5 mg of pindolol in the evening. A skilled practitionerwould be expected to determine the precise level of dosing. The ideadosing would be routinely determined by an evaluation of the patient andthe needs of the patient.

[0020] This patent application describes the treatment of numerousconditions, disorders, diseases, and disease symptoms with thecombination of drugs described herein, in addition to the conditions,disorders, diseases, and disease symptoms described above, the followingmay also be treated with these drugs: Addictive Disorders, PsychoactiveSubstance Use Disorders, Nicotine Addition or Tobacco Addiction (with aresult of Smoking Cessation or a decrease in smoking) and AttentionDeficit Hyperactivity Disorder (ADHD). This patent application alsodescribes the treatment of Obsessive Compulsive Disorders (OCD), andPanic Disorder (PD), comprising administering a therapeuticallyeffective, nontoxic dose of the drugs described herein and derivativesand or pharmaceutically acceptable salts thereof to a patient.

[0021] Addictive Disorders and Psychoactive Substance Use Disorders,such as Intoxication disorders, Inhalation disorders, Alcohol addiction,Tobacco Addiction and or Nicotine Addiction. Tobacco and Nicotineaddiction would be treated with the goal of achieving either SmokingCessation or Smoking Reductions.

[0022] Addictive Disorders, Alcohol and Other Psychoactive Substance UseDisorders, disorders related to Intoxication and Inhalants andespecially Tobacco Addiction or Nicotine Addiction, may be treated withthe drugs described herein. Tobacco Addiction or Nicotine Addictionwould be treated with the drugs described herein in order to achievesmoking/chewing cessation or smoking/chewing reduction. Generaldescriptions of Addictive Disorders, including disorders related toIntoxication and Inhalants and Tobacco Addiction or Nicotine Addictionmay be found in many standard sources, such as, The American PsychiatricPress Textbook of Psychiatry, Second Edition, Edited by Robert E. Hales,Stuart C. Yudofsky, and John A. Talbott, copyright 1994, incorporated byreference, especially pp. 401 et. seq., section on “Nicotine”incorporated by reference. Another of many texts is the Manual ofPsychiatric Therapeutics, Second Edition, edited by Richard I. Shader,incorporated by reference, especially pp. 85 from Chapter 11 (Hypnosis).

[0023] The treatment of Alcohol and Other Psychoactive Substance UseDisorders, such as disorders related to Intoxication and Inhalants andTobacco Addiction or Nicotine Addiction but especially Tobacco Addictioninvolves the administration of the drugs described herein in a mannerand form that provide a reduction in the symptoms of the disease.Tobacco Addiction or Nicotine Addiction in particular would be treatedto achieve a reduction or cessation of smoking or chewing of nicotinecontaining materials by a patient. Cessation or a reduction in smokingor chewing of addictive or psychoactive substances involves theadministration of the drugs described herein in a manner and form thatprovide a reduction in the symptoms of the disease, or with Tobacco orNicotine with a reduction in the amount smoked or chewed.. See thegeneral description above for administration of Reboxetine.

Attention Deficit Hyperactivity Disorder (ADHD)

[0024] ADHD is a condition or disease state that may be treated with thedrugs described herein. General descriptions of ADHD, may be found inmany standard sources, such as, The American Psychiatric Press Textbookof Psychiatry, Second Edition, Edited by Robert E. Hales, Stuart C.Yudofsky, and John A. Talbott, copyright 1994, incorporated byreference, especially pp. 741 et. al., section on “ADHD,” incorporatedby reference. Another of many texts is the Manual of PsychiatricTherapeutics, Second Edition, edited by Richard I. Shader, incorporatedby reference, especially Chapter 18, Attention-Deficit hyperactivityDisorder, and pp. 172 et. seq., incorporated by reference.

[0025] The treatment of Attention Deficit Hyperactivity Disorder inchildren and adults involves the administration of the drugs describedherein in a manner and form that provide a reduction in the symptoms ofthe disease. A child or young adult may require a smaller dosagedepending upon the size, age, condition of the patient. See generaldescription above for administration of the drugs described herein.

Obsessive Compulsive Disorders (OCD)

[0026] Obsessive Compulsive Disorder is a condition or state of anxietythat may be treated with reboxetine. General descriptions of OCD, may befound in many standard sources, such as, The American Psychiatric PressTextbook of Psychiatry, Second Edition, Edited by Robert E. Hales,Stuart C. Yudofsky, and John A. Talbott, copyright 1994, incorporated byreference, especially the chapter on “Anxiety Disorders,” incorporatedby reference. Another of many texts is the Manual of PsychiatricTherapeutics, Second Edition, edited by Richard I. Shader, incorporatedby reference, especially Chapter 5, Obsessions and Compulsions, moreparticularly, Section III of that chapter, “OCD” pp. 36 et. seq.,incorporated by reference.

[0027] The treatment of Obsessive Compulsive Disorders (OCD) involvesthe administration of reboxetine in a manner and form that provide areduction in the symptoms of the disease. See general description abovefor administration of reboxetine.

[0028] The following study shows the therapeutic effectiveness of usingreboxetine in doses varying from 6 to 8 mg to treat OCD. This study isprovided to illustrate the usefulness of using reboxetine as a treatmentfor OCD and the invention described herein should not be consideredlimited by this example.

[0029] In a trial involving 10 patients with a DSM-III-R diagnosis ofObsessive Compulsive Disorder who were all treated with reboxetine for aperiod of 3 to 4 weeks with the dose for the first week at 6 mg (4 mg ina.m. and 2 mg in p.m.) with the dose increasing in the second week to 8mg (4 mg b.i.d.). At CGI last assessment, one patient was judged verymuch improved, 4 were judged much improved, 2 minimally improved, while3 were unchanged. Of the patients who did respond they had a decrease ofthe obsessive-compulsive symptomatology, as measured by the CPRS-OCrating scale, of more than 30 and as much as 73%.

Panic Disorder (PD)

[0030] Panic Disorder is a condition or state of anxiety that may betreated with reboxetine. General descriptions of PD, may be found inmany standard sources, such as, The American Psychiatric Press Textbookof Psychiatry, Second Edition, Edited by Robert E. Hales, Stuart C.Yudofsky, and John A. Talbott, copyright 1994, incorporated byreference, especially the chapter on “Anxiety Disorders,” incorporatedby reference, another of many texts is the Manual of PsychiatricTherapeutics, Second Edition, edited by Richard I. Shader, incorporatedby reference, especially Chapter 25, “Approaches to the Treatment ofAnxiety States,” incorporated by reference.

[0031] The treatment of Panic Disorder involves the administration ofthe drugs described herein in a manner and form that provide a reductionin the symptoms of the disease. See general description above.

1. A single dosage form of reboxetine and pindolol.
 2. The single doseof claim 1 where the form is a tablet, hard or soft capsule or caplet.3. The single dose of claim 1 where the amount of reboxetine is 5 mg andthe amount of pindolol is 7.5 mg.
 4. A method of treating a patientexperiencing symptoms selected from; depression, general anxietydisorders (GADs), Addictive Disorders, attention deficit hyperactivitydisorder (ADHD), and anxiety disorders such as obsessive compulsivedisorder (OCD), panic disorder (PD), social phobia (SP), comprising theadministration of a therapeutically effective, nontoxic dose ofpindolol, its derivatives and or pharmaceutically acceptable saltsthereof to a patient and administering a therapeutically effective,nontoxic dose of a selective, a noradrenaline reuptake inhibitor (NARI),its derivatives and or pharmaceutically acceptable salts thereof to apatient.
 5. A method of treating a patient as in claim 4 where thenoradrenaline reuptake inhibitor (NARI) is reboxetine.
 6. A method oftreating a patient as in claim 5 where the administration of the dose ofpindolol is administered within 24 hours of the administration of thedose of reboxetine.
 7. The method of claim 6 where the pindolol isadministered within 12 hours of the reboxetine.
 8. The method of claim 7where the pindolol is administered within 6 hours of the reboxetine. 9.The method of claim 8 where the pindolol is administered within 3 hoursof the reboxetine.
 10. The method of claim 9 where the pindolol isadministered within 1 hour of the reboxetine.
 11. The method of claim 10where the pindolol and reboxetine are administered concomitantly. 12.The method of claim 5 where the patient is experiencing symptoms ofdepression.
 13. The method of claim 5 where the patient is experiencingsymptoms of general anxiety disorders (GADs).
 14. The method of claim 5where the patient is experiencing symptoms of Addictive Disorders. 15.The method of claim 5 where the patient is experiencing symptoms ofattention deficit hyperactivity disorder (ADHD).
 16. The method of claim5 where the patient is experiencing symptoms of obsessive compulsivedisorder (OCD).
 17. The method of claim 5 where the patient isexperiencing symptoms of panic disorder (PD).
 18. The method of claim 5where the patient is experiencing symptoms of social phobia (SP). 19.The use of reboxetine and pindolol, their derivatives and orpharmaceutically acceptable salts thereof in the manufacture of amedicament comprising an effective, nontoxic dose of reboxetine andpindolol to treat general anxiety disorders (GADs), Addictive Disorders,attention deficit hyperactivity disorder (ADHD), and anxiety disorderssuch as obsessive compulsive disorder (OCD), panic disorder (PD), socialphobia (SP), and/or for the treatment of any of the symptoms of thosediseases.
 20. The method or use in claims 1-19 where the reboxetine doserange is from about 4 to 10 mg. per patient per day and the pindololdose range is from about 10 to 20 mg. per patient per day, deliveredtwice a day.
 21. The method or use in claims 1-19 where the reboxetinedose range is from about 6 to 8 mg. per patient per day and the pindololdose range is from about 10 to 16 mg. per patient per day, deliveredtwice a day.